ABSTRACT Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder characterized by diffuse arteriovenous malformations (AVMs) and telangiectasia that affect many organs. The most common manifestations of HHT are epistaxis and GI bleeding; however AVMs that involve the lungs, brain or liver can also lead to devastating cardiovascular complications including congestive heart failure, pulmonary hemorrhage and hemorrhagic stroke. Estimates suggest a prevalence of more than 100,000 cases of HHT in the US. In addition to bleeding and cardiovascular manifestations, the morbidity of HHT leads to a high incidence of anxiety and depression that greatly affects social function. There is no broadly-accepted, effective therapy for HHT. Ablation of HHT lesions via interventional approaches is commonly used but provides only transient benefit. Medical approaches have included anti-fibrinolytic therapy, estrogen, and octreotide, among others, however these are not effective in most patients. A recent study demonstrated that nasal sprays containing tranexamic acid, estriol or bevacizumab were no more effective than placebo in treating HHT-associated epistaxis. The current study builds upon results of several small studies that suggest efficacy of thalidomide in HHT; however, thalidomide is not available for clinical trials in the U.S. Thus, we propose to study pomalidomide, a third generation thalidomide analogue with similar anti-angiogenic activity but less toxicity that thalidomide. A small, industry-funded pilot study by the PI has demonstrated efficacy and safety of pomalidomide in HHT, and the FDA has issued an IND to expand these observations. This resubmission proposes a randomized, placebo-controlled study developed with support from an NHLBI U34 Clinical Trial Planning Grant and U24 Clinical Trials Development Resource for Hematologic Disorders by a team of HHT experts, a patient advocate, and experienced clinical trial statisticians. The same team that designed the study will conduct it, using a sIRB at the Cleveland Clinic. We propose to 1) determine the efficacy and safety of pomalidomide in patients with HHT and epistaxis requiring periodic iron infusion or blood transfusion, 2) determine the effect of pomalidomide on quality of life in patients with HHT using NIH PROMIS tools and an HHT-specific questionnaire, and 3) create a biorepository of samples from study patients for future biomarker and mechanistic studies. This study may validate pomalidomide as a new therapeutic option and change the paradigm for treatment of HHT.